Thursday, February 5, 2015

Venomous Insulin: Cone Snails and Their Specialized Chemical-Weapon

By Diana Zafra

As a biologist with a sweet toothwho consumes more sugar than any
dentist would approve of, I’m amazed with how the beta-cells in my pancreas responds
to the high glucose levels, in my blood, with the release of insulin. Insulin is a necessary regulatory hormone that transports and stores glucose into our cells for the
production of energy.

Although
insulin is necessary for regulating glucose in the blood from getting too high
(hyperglycemia) or too low (hypoglycemia), there is a dark side to this
hormone. I was pretty intrigued when I read about a recent experiment that discovered its use as a chemical-weapon. Just think about that:
insulin is used in nature to kill. Cone snails produce a
cocktail of neurotoxins that include large amounts of insulin, to facilitate
predation.

Brief Introduction to Cone Snails

Two species of cone snail that have net-like mouths to swallow prey

In the genus Conus, members usually have
two mechanisms of secreting their venom. Some members inject their venom by harpooning fish while the second mechanism involves releases
of venom into the surrounding area when they detect fish nearby.

Conus produce
conotoxin, or venom, that targets the nervous system and is produced in a long
venom duct, similar to a “hypodermic needle,” used to inject its prey. The red
part in the picture below is where the insulin and conotoxins are located.

Safavi-Hemami et al. PNAS 2014.

Hu et al. BMC Genomics 2012.

The most dangerous species of cone snail is Conus
geographus, and they have a net-like false mouth to swallow their prey whole. In order to catch their faster swimming prey,
such as schools of fish, they release the nirvana cabal, the toxin combination of
venoms released, to disorient and slow them down. This allows the snail to make
its way towards the fish and engulf them whole. After a couple of hours, they
regurgitate the scales and bones, while digesting their soft tissue (Yum!).

Experiments on Zebrafish

The use of venom by cone snails to paralyze their
prey is no novelty and recordings date back to 1956. However, a recent experiment
conducted by Dr. Helena Safavi-Hemami, from The University of Utah, discovered that within the nirvana cabal, there was a high presence of insulin in the dorsal
end of the needle inside of the snail. In the experiment, the venom of C. geographus was both
injected directly into zebrafish and released into the water columns in
which zebrafish larvae were then observed for changes in mobility.

Zebrafish! Aren't they cute?

When analyzing the individual components in the
venom, they discovered two main types of insulin. One type, labeled conus
insulin 1 (Con-Ins-G1) made up 99% of the distal end of the injection tip. This
immobilized zebrafish when injected due to glucose levels falling far
below what is necessary for the cells to properly function, otherwise known as
a hypoglycemic shock.

Fig 5A Showing insulin activity in zebrafish

The
graph above depicts the results of an experiment where zebrafish blood glucose was
measured prior to any treatment (baseline group). Then they were injected with streptozotocin
(STZ), which is an agent used to induce hyperglycemia. That’s when the higher
glucose levels in the blood are observed (p<.01). Shortly afterwards, the
STZ injected zebrafish were injected with human insulin, while others were
injected with the snail cone insulin and both significantly (P< .003)
reduced the blood glucose levels.

When the Con-Ins-G1 was added to the water,
they observed zebrafish larvae swimming much slower than the control group,
where no insulin was added. (Select the link below to see the effects!)

It appears that the insulin in their venom is
tailored to match their prey’s insulin. The insulin in their venom matches fish
insulin more than molluscan insulin. Expression of insulin in most mollucs is primarily
expressed in their cells that make up their nervous system such as neurons and cerebral ganglia. The insulin
in the venom is believed to activate the other chemical compounds of the nirvana cabal and induce hypoglycemic shock on its prey. This insulin is also much smaller
than that discovered on any other organism, which scientists speculate allows
for its quick action. This is the first time insulin has been documented to be used as venom in
nature.

Although Conus geographus measure only between
4-6 inches in size, its venom is so powerful that there have been instances of
human deaths from accidental encounters. In humans, plunging drops in glucose
result in disorientation, unconsciousness, and eventually death by respiratory
paralysis, if left untreated. This snail was even coined “cigarette snail”
because old tales claimed that if stung by one of these snails, you'd be dead before you finished smoking a cigarette.

The Future of This Novel Insulin

So how could these types of studies ever come to
relate to people? Why should we be interested in this venomous insulin? These
types of studies could lead to new pharmaceuticals.

A drug resulted from gila monster venom!

It wouldn't be the first
time since the discovery of exendin-4 protein from venom in gila monsters
resulted in the development of the commercial drug exenatide, used to treat
diabetes mellitus. Exendin-4 isn't insulin and varies from the mechanism of
cone snail insulin because it causes its prey to overproduce its own insulin. Yet
these types of studies may help scientists understand how insulin size could
influence its action and could help with use for drug therapies. As with most
exciting novelties in science, further studies for this novel insulin will
likely be focused on finding out the the genes responsible for the production
of this deadly insulin.

Safavi-Hemami, et al. 2014. Specialized insulin
is used for chemical warfare by fish hunting cone snails. Proceedings of the
National Academy of Sciences published ahead of print January 20, 2015,
doi:10.1073/pnas.1423857112.